Basic Science and Pathogenesis
The microtubule-associated protein tau is the most commonly misfolded protein in neurodegenerative disorders including Alzheimer's disease and other related tauopathies. These neurological illnesses are hypothesized to share a common mechanism of disease progression, where pathogenic aggregates...
Gespeichert in:
| Veröffentlicht in: | Alzheimer's & dementia Jg. 20 Suppl 1; S. e089660 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
| Veröffentlicht: |
United States
01.12.2024
|
| Schlagworte: | |
| ISSN: | 1552-5279 |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Abstract | The microtubule-associated protein tau is the most commonly misfolded protein in neurodegenerative disorders including Alzheimer's disease and other related tauopathies. These neurological illnesses are hypothesized to share a common mechanism of disease progression, where pathogenic aggregates or 'seeds' of the tau protein function as templates promoting misfolding of functional, soluble tau protein. Under this premise, therapeutic strategies that modulate the seeding cascade, have high potential to interfere with the disease process.
While increasing evidence is emerging that tau pathology progression is based on seeding and spreading mechanisms reminiscent of prion protein pathology, an in-depth understanding of the cellular pathways and cofactors that drive disease progression is, however, still lacking. In order to identify tau seeding modulators, a previously described HEK293T biosensor cell line
was applied, able to sensitively detect tau seeding. To understand the self-propagation process, I exploited this cell model to performed a pooled genome-wide loss-of-function CRISPR screen
, allowing the identification of proteins that robustly influence tau seeding.
Amongst the top hits were many genes involved in autophagy and specifically autophagosome formation. Building on these insights, I am working towards a mechanistic understanding how the loss of function of the ATG genes impacts tau seeding in mammalian cells and in a Drosophila melanogaster model.
Together, my in vitro and in vivo studies are starting to unravel the molecular details of the interplay between tau seeding and autophagy. These studies have the ability to reveal novel strategies to reduce the toxicity of tau aggregates by stimulating the activity of the autophagic machinery. Research approaches addressing tau in general, and tau seeding more specifically, have enormous potential to provide highly innovative, disease-modifying first-in-class therapeutics for AD. References 1) Holmes BB et al. (2014) "Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci USA. 111: E4376-E4385 2) Doench JG et al. (2016) "Optimized sgRNA design to maximise activity and minimise off-target effects of CRISPR-Cas9." Nat. Biotechnol. 34: 184-191. |
|---|---|
| AbstractList | The microtubule-associated protein tau is the most commonly misfolded protein in neurodegenerative disorders including Alzheimer's disease and other related tauopathies. These neurological illnesses are hypothesized to share a common mechanism of disease progression, where pathogenic aggregates or 'seeds' of the tau protein function as templates promoting misfolding of functional, soluble tau protein. Under this premise, therapeutic strategies that modulate the seeding cascade, have high potential to interfere with the disease process.
While increasing evidence is emerging that tau pathology progression is based on seeding and spreading mechanisms reminiscent of prion protein pathology, an in-depth understanding of the cellular pathways and cofactors that drive disease progression is, however, still lacking. In order to identify tau seeding modulators, a previously described HEK293T biosensor cell line
was applied, able to sensitively detect tau seeding. To understand the self-propagation process, I exploited this cell model to performed a pooled genome-wide loss-of-function CRISPR screen
, allowing the identification of proteins that robustly influence tau seeding.
Amongst the top hits were many genes involved in autophagy and specifically autophagosome formation. Building on these insights, I am working towards a mechanistic understanding how the loss of function of the ATG genes impacts tau seeding in mammalian cells and in a Drosophila melanogaster model.
Together, my in vitro and in vivo studies are starting to unravel the molecular details of the interplay between tau seeding and autophagy. These studies have the ability to reveal novel strategies to reduce the toxicity of tau aggregates by stimulating the activity of the autophagic machinery. Research approaches addressing tau in general, and tau seeding more specifically, have enormous potential to provide highly innovative, disease-modifying first-in-class therapeutics for AD. References 1) Holmes BB et al. (2014) "Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci USA. 111: E4376-E4385 2) Doench JG et al. (2016) "Optimized sgRNA design to maximise activity and minimise off-target effects of CRISPR-Cas9." Nat. Biotechnol. 34: 184-191. |
| Author | Böddrich, Annett Nevado, Juan Carlos Company Gargiulo, Gaetano Schmitt, Matthias Jürgen Brusendorf, Lydia Diez, Lisa Wegmann, Susanne Wanker, Erich Beetz, Stephanie Deckert, Annika Serresi, Michela |
| Author_xml | – sequence: 1 givenname: Annika surname: Deckert fullname: Deckert, Annika organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany – sequence: 2 givenname: Annett surname: Böddrich fullname: Böddrich, Annett organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany – sequence: 3 givenname: Lisa surname: Diez fullname: Diez, Lisa organization: DZNE German Center for Neurodegenerative Diseases, Berlin, Germany – sequence: 4 givenname: Matthias Jürgen surname: Schmitt fullname: Schmitt, Matthias Jürgen organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany – sequence: 5 givenname: Juan Carlos Company surname: Nevado fullname: Nevado, Juan Carlos Company organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany – sequence: 6 givenname: Stephanie surname: Beetz fullname: Beetz, Stephanie organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany – sequence: 7 givenname: Lydia surname: Brusendorf fullname: Brusendorf, Lydia organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany – sequence: 8 givenname: Michela surname: Serresi fullname: Serresi, Michela organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany – sequence: 9 givenname: Susanne surname: Wegmann fullname: Wegmann, Susanne organization: DZNE German Center for Neurodegenerative Diseases, Berlin, Germany – sequence: 10 givenname: Gaetano surname: Gargiulo fullname: Gargiulo, Gaetano organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany – sequence: 11 givenname: Erich surname: Wanker fullname: Wanker, Erich organization: Max Delbrück Center for Molecular Medicine, Berlin, Germany |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/39751117$$D View this record in MEDLINE/PubMed |
| BookMark | eNo1zstKA0EQQNFCFPPQjR8Q5gcmVvVzaqnBFwQUzD50d6p1JOkM6bjQr3ehru7ucCdwWvZFAK4I54SorsP2e44dO4cnMCZrVWuV5xFMav1ANNiRPYeRZm-JyI9hdhtqn5rX1EtJ0oSyaV7C8X3_JkVqXy_gLIdtlcu_TmF1f7daPLbL54enxc2yHVgf2xSyEYpOee2zRnJolLHCxmQO2iFjwhwtR-Vi7pQYwi7F7BVntlklPYXZLzt8xp1s1sOh34XD1_r_U_8A9UY8mQ |
| ContentType | Journal Article |
| Copyright | 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. |
| Copyright_xml | – notice: 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. |
| DBID | CGR CUY CVF ECM EIF NPM |
| DOI | 10.1002/alz.089660 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) |
| DatabaseTitleList | MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| EISSN | 1552-5279 |
| ExternalDocumentID | 39751117 |
| Genre | Journal Article |
| GroupedDBID | --- --K --M .~1 0R~ 1B1 1OC 1~. 1~5 24P 33P 4.4 457 4G. 53G 5VS 7-5 71M 7RV 7X7 8FI 8FJ 8P~ AACTN AAEDT AAHHS AAIKJ AAKOC AALRI AANLZ AAOAW AAXLA AAXUO AAYCA ABBQC ABCQJ ABCUV ABIVO ABJNI ABMAC ABMZM ABUWG ABWVN ACCFJ ACCMX ACCZN ACGFS ACGOF ACPOU ACRPL ACXQS ADBBV ADBTR ADEZE ADHUB ADKYN ADMUD ADNMO ADPDF ADVLN ADZMN ADZOD AEEZP AEIGN AEKER AENEX AEQDE AEUYR AEVXI AFKRA AFTJW AFWVQ AGHFR AGUBO AGWIK AGYEJ AITUG AIURR AIWBW AJBDE AJOXV AJRQY AKRWK ALMA_UNASSIGNED_HOLDINGS ALUQN AMFUW AMRAJ AMYDB ANZVX AZQEC BENPR BFHJK BLXMC C45 CCPQU CGR CUY CVF DCZOG EBS ECM EIF EJD EMOBN EO8 EO9 EP2 EP3 F5P FDB FEDTE FIRID FNPLU FYUFA G-Q GBLVA HMCUK HVGLF HX~ HZ~ IHE J1W K9- LATKE LEEKS M0R M41 MO0 MOBAO N9A NAPCQ NPM O-L O9- OAUVE OVD OVEED OZT P-8 P-9 P2P PC. PGMZT PIMPY PSYQQ Q38 QTD RIG ROL RPM RPZ SDF SDG SEL SES SSZ SUPJJ T5K TEORI UKHRP ~G- |
| ID | FETCH-LOGICAL-p93t-caf4e1b62737f301604245e944f9a36090c0fb59b26bf82e4108cbf729f95f2c3 |
| IngestDate | Wed Feb 19 02:03:26 EST 2025 |
| IsPeerReviewed | true |
| IsScholarly | true |
| Language | English |
| License | 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. |
| LinkModel | OpenURL |
| MergedId | FETCHMERGED-LOGICAL-p93t-caf4e1b62737f301604245e944f9a36090c0fb59b26bf82e4108cbf729f95f2c3 |
| PMID | 39751117 |
| ParticipantIDs | pubmed_primary_39751117 |
| PublicationCentury | 2000 |
| PublicationDate | 2024-Dec |
| PublicationDateYYYYMMDD | 2024-12-01 |
| PublicationDate_xml | – month: 12 year: 2024 text: 2024-Dec |
| PublicationDecade | 2020 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Alzheimer's & dementia |
| PublicationTitleAlternate | Alzheimers Dement |
| PublicationYear | 2024 |
| SSID | ssj0040815 |
| Score | 2.4102137 |
| Snippet | The microtubule-associated protein tau is the most commonly misfolded protein in neurodegenerative disorders including Alzheimer's disease and other related... |
| SourceID | pubmed |
| SourceType | Index Database |
| StartPage | e089660 |
| SubjectTerms | Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer Disease - pathology Animals Autophagy - physiology Drosophila melanogaster HEK293 Cells Humans tau Proteins - metabolism Tauopathies - genetics Tauopathies - pathology |
| Title | Basic Science and Pathogenesis |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/39751117 |
| Volume | 20 Suppl 1 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| journalDatabaseRights | – providerCode: PRVPQU databaseName: Consumer Health Database databaseCode: M0R dateStart: 20240101 customDbUrl: isFulltext: true eissn: 1552-5279 dateEnd: 99991231 titleUrlDefault: https://search.proquest.com/familyhealth omitProxy: false ssIdentifier: ssj0040815 providerName: ProQuest – providerCode: PRVPQU databaseName: Health & Medical Collection databaseCode: 7X7 dateStart: 20240101 customDbUrl: isFulltext: true eissn: 1552-5279 dateEnd: 99991231 titleUrlDefault: https://search.proquest.com/healthcomplete omitProxy: false ssIdentifier: ssj0040815 providerName: ProQuest – providerCode: PRVPQU databaseName: Nursing & Allied Health Database databaseCode: 7RV dateStart: 20240101 customDbUrl: isFulltext: true eissn: 1552-5279 dateEnd: 99991231 titleUrlDefault: https://search.proquest.com/nahs omitProxy: false ssIdentifier: ssj0040815 providerName: ProQuest – providerCode: PRVPQU databaseName: ProQuest Central databaseCode: BENPR dateStart: 20240101 customDbUrl: isFulltext: true eissn: 1552-5279 dateEnd: 99991231 titleUrlDefault: https://www.proquest.com/central omitProxy: false ssIdentifier: ssj0040815 providerName: ProQuest – providerCode: PRVPQU databaseName: Publicly Available Content Database databaseCode: PIMPY dateStart: 20240101 customDbUrl: isFulltext: true eissn: 1552-5279 dateEnd: 99991231 titleUrlDefault: http://search.proquest.com/publiccontent omitProxy: false ssIdentifier: ssj0040815 providerName: ProQuest – providerCode: PRVWIB databaseName: Wiley-Blackwell Open Access Collection databaseCode: 24P dateStart: 20240101 customDbUrl: isFulltext: true eissn: 1552-5279 dateEnd: 99991231 titleUrlDefault: https://authorservices.wiley.com/open-science/open-access/browse-journals.html omitProxy: false ssIdentifier: ssj0040815 providerName: Wiley-Blackwell |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwtV3JTsMwELVKQagXBGLflAO3quA4cRwfWxYBAoSgB27IMTaNaNOIFIT4esbO0ohFggMXK0piR_GLJ-_ZnhmE9jzqS0oiUKoMhhtYP9kRVINKCZTyIymAYds4sxfs6iq8u-PXjcZZ6QvzOmRJEr698fRfoYZzALZxnf0D3FWjcAKOAXQoAXYofwV8T0DHV2PWOgMAyxs_GqMWZ3Uy2h2-D1Rs06ewzH4DD3ayMK5M9ZGqnHq6SRI_TdW7WWDvBSY5e55Lqmvce6otNEdxPjF9EWdVlVs5GBVLUTbJeCyy9rlt5tA4gNanH4hf28qhCpNJjZzNU8KUNpXgts1K2nZrxlHh0MQC_dZw54FgxfB9_-tN0L_pyKIF5AkIYu7s-SlMdnlpBs0SRrnZ3XeJb8qfsg_Mh1bRacnB9EEtNF9W_aQsLMPoL6KFQho43RzSJdRQyTLatXA6BZwOwOnU4VxB_ZPj_uFpp8hp0Um5N-lIoX3lRgGQRqY9E93PrDwr7vuaCy_AHEusI8ojEkQ6JMp3cSgjDQpIc6qJ9FZRMxknah05rtI68FyBYTxB9YgL6ioQi4QxFmCBN9Ba_jb3aR635L58z80fr2yh1hTjbdScPL-oHTQnXydx9rxre_QDfE8pvg |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Basic+Science+and+Pathogenesis&rft.jtitle=Alzheimer%27s+%26+dementia&rft.au=Deckert%2C+Annika&rft.au=B%C3%B6ddrich%2C+Annett&rft.au=Diez%2C+Lisa&rft.au=Schmitt%2C+Matthias+J%C3%BCrgen&rft.date=2024-12-01&rft.eissn=1552-5279&rft.volume=20+Suppl+1&rft.spage=e089660&rft_id=info:doi/10.1002%2Falz.089660&rft_id=info%3Apmid%2F39751117&rft.externalDocID=39751117 |